Expert Critique

The use and interpretation of imaging in non-small cell lung cancer (NSCLC) have become more complicated in the era of immunotherapy and other new treatments. For example, when immunotherapy is used, tumor growth and the appearance of new lesions may indicate pseudoprogression rather than a true progression of disease, in which situation continuation of therapy is reasonable. The development of immune-related response criteria (irRC) has created a more reliable way to evaluate the activity of immunotherapy agents. Another example is measuring exosomes for detecting early progression of disease; it can also be used as a potential imaging marker for pre-metastatic tissue priming. A specific exosomal protein (s100A8/A9), known to promote angiogenesis, immune suppression, and the development of metastasis, can now be traced using SPECT imaging technique at an early stage of the metastatic process, before metastases can be detected by conventional imaging modalities.

Full Critique

Non-invasive imaging of non-small cell lung cancer (NSCLC) immunotherapy treatment has been described as an "elegant opportunity to obtain quantitative and kinetic information." But elegant and simple don't always go hand-in-hand, and this type of imaging has its own set of criteria when performing data interpretation.

Fortunately, imaging specialists are addressing the unique challenges of an immunotherapy-based imaging workup, both for the present and the future.

Pseudoprogression

Imaging interpretation of NSCLC response for conventional therapies relies on World Health Organization criteria and the revised Response Evaluation Criteria in Solid Tumors (RECIST 1.1). For years, these documents have reliably served the radiology and oncology communities and guided the therapeutic regimen.

"On the basis of both sets of criteria, tumor growth, the appearance of new lesions after initiation of antitumor therapy, or both are considered disease progression, which is typically equated with drug failure and prompts consideration of a cessation or change in therapy," noted Florian Fintelmann, MD, of Massachusetts General Hospital in Boston, and colleagues.

Assessment based on these criteria "is reliable with traditional cytotoxic therapy, where the effect of the treatment is expected to occur soon after initiation," the team explained.

However, NSCLC immunotherapy may produce an atypical response pattern known as pseudoprogression. "This atypical response pattern has been attributed to continued tumor growth while awaiting development of an adequate immune response, immune cell infiltrate of either known or radiologically occult lesions, or both."

If WHO and RECIST 1.1 criteria are being applied to the imaging evaluation of these patients, a recommendation to cease treatment could be put forward before they could mount a response to their immunotherapy.

Recognizing this potential hazard, Jedd Wolchok, MD, chair of Clinical Investigation and chief of the Melanoma & Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center in New York City, and colleagues proposed the immune-related response criteria (irRC) as a scoring system for a more reliable way to evaluate the activity of immunotherapy agents.

According to Fintelmann's group, there are two major differences between conventional tumor response criteria and irRC. First, new lesions are not automatically indicative of progressive disease (PD) and are incorporated into the total tumor burden. The second is that an increase in total tumor burden must be confirmed by two consecutive imaging studies performed a minimum of 4 weeks apart before a PD designation can be applied.

Wolchok's group applied the irRC criteria to a pair of phase II ipilimumab (Yervoy) studies for advanced melanoma and found a discordance in pinpointing PD.

"These analyses show that 9.7% (22 of 227) of treated patients, who were initially characterized as PD by WHO criteria, have evidence of activity consistent with a response to ipilimumab. This suggests that a measurable clinical effect can be present in a subset of patients with an early increase in tumor burden and/or the appearance of new lesions."

Although irRC guidelines mandate that an increase in total tumor burden be confirmed by consecutive imaging studies 4 weeks apart, "no formal consensus statement exists that provides details regarding a fixed imaging follow-up schedule for patient with NSCLC who are receiving immunotherapy."

Exosomes

At the 2016 Future Horizons in Lung Cancer conference, Tony Ng, MD, PhD, of Kings College London, spoke on the up-and-coming imaging techniques in NSCLC, focusing on monitoring tumor response with circulating exosomes.

Exosomes are specialized membranous nano-sized vesicles derived from endocytic compartments that are released by many cell types, according to Anoek Zomer, PhD, from VU University Medical Center in Amsterdam, and colleagues.

Her group proposed that exosomes are an intercellular (miRNA-based) mode of signal transmission that may be well suited in controlling space-confined processes such as the initiation of immune responses in the secondary (peripheral) lymphoid tissues or in a tumor microenvironment.

Ng reported on patients treated with the third-generation epidermal growth factor (EGFR) inhibitor osimertinib (Tagrisso) who relapsed due to increased HER3 expression. Researchers at his lab used a HER3 radiotracer for PET imaging that was able to monitor the development of immunotherapy resistance via circulating exosomes in the blood, rather than waiting for the appearance of tumor growth.

Taken together, the work by Ng's group highlights the potential for monitoring disease progression with exosomes, while Zomer et al suggest the possibility that exosomes may have application for detecting early progression of disease.

Their work looked at the release of S100A8/A9 -- an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression -- by myeloid-derived suppressor cells (MDSC). The team conducted single-photon emission computed tomography (SPECT) imaging with an S100A9-specific antibody labeled with Indium-111 in mice implanted with 4T1.2 and 67NR tumors.

The 4T1.2 tumors are known to form metastasis in lungs and bones and 67NR tumors grow without shedding cells systemically. S100A9-specific SPECT imaging showed a higher tracer uptake in lungs, spleen, and tumor of the mice implanted with metastatic 4T1.2, as compared with non-metastatic 67NR and non-tumor-bearing control mice.

"S100A8/A9 release was evident and detectable at an early stage of the metastatic process before tumor cells seeded in the lungs of 4T1.2 tumor-bearing mice," the authors wrote.

Eisenblaetter's group said they believe that S100A8/A9 in vivo imaging may prove useful as a way to non-invasively address tumor immune crosstalk to optimize immunotherapy in human patients: "Clinical establishment of this technique could change how patients are selected for and monitored during therapy."

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